Biomarker and Method for Predicting Sensitivity to MET Inhibitors

Abstract

Methods for determining the responsiveness of a Met-related cancer in a subject to treatment with a Met inhibitor. Kits for performing the disclosed methods are also provided. The present invention also provides a method of treating glioblastomamultiforme (GBM) in a subject in need thereof, the method comprises administering a therapeutically effective dose of a Met inhibitor in combination with a therapeutically effective dose of a epithelial growth factor receptor (EGFR) inhibitor.

1 . A method for determining the responsiveness of a Met-related cancer in a subject to treatment with a Met inhibitor, the method comprising:
 in a subject having or suspected of having a Met-related cancer, detecting whether the Met-related cancer is HGF-autocrine;   wherein if the Met-related cancer is HGF-autocrine, determining that the Met-related cancer will be responsive to treatment with a Met inhibitor.   
     
     
         2 . The method according to  claim 1 , wherein the detecting step further comprises:
 (a) obtaining a biological sample from the subject;   (b) measuring the level of expression of HGF in the biological sample; and   (c) comparing the level of expression of HGF present in the biological sample to a reference sample,   wherein, if the level of expression of HGF in the biological sample is different from the level of expression of HGF in the reference sample, then the Met-related cancer is HGF-autocrine.   
     
     
         3 . The method according to  claim 2 , wherein the obtaining the biological sample from the subject is selected from the group consisting of: obtaining a blood sample from the subject, obtaining a tumor tissue specimen from the subject, obtaining a cerebral spinal fluid (CSF) sample from the subject, or combinations thereof. 
     
     
         4 . The method according to  claim 3 , wherein a tumor tissue specimen is obtained from the subject. 
     
     
         5 . The method according to  claim 4 , wherein a tumor tissue biopsy or a surgically resected tumor tissue sample is obtained from the subject. 
     
     
         6 . The method according to  claim 2 , the measuring step further comprises contacting the biological sample with an HGF-binding reagent under conditions that promote the binding of HGF with the HGF-binding reagent 
     
     
         7 . The method according to  claim 6 , wherein the HGF-binding reagent is selected from the group consisting of: an anti-HGF antibody, a nucleic acid operable to hybridize to at least a portion of an HGF gene, an HGF binding protein, and combinations thereof. 
     
     
         8 . The method according to  claim 7 , wherein the HGF-binding reagent is labeled with a detectable tag. 
     
     
         9 . The method according to  claim 8 , wherein the detectable tag is selected from the group consisting of: a fluorophore, a radioligand, a chemilluminescence molecule, a conjugated enzyme, a peptide conjugate molecule, and combinations thereof. 
     
     
         10 . The method according to  claim 7 , wherein an anti-HGF antibody is conjugated with a fluorophore. 
     
     
         11 . The method according to  claim 10 , wherein the fluorophore is selected from the group consisting of: fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2′,7′-dimethoxy-4′,5′-dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) and N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA) 
     
     
         12 . The method according to  claim 7 , wherein a radioligand is conjugated to at least one of an anti-HGF antibody, a nucleic acid operable to hybridize to at least a portion of a HGF gene, and a HGF binding protein. 
     
     
         13 . The method according to  claim 7 , wherein a conjugated enzyme is selected from the group consisting of: horseradish peroxidase, glucose oxidase, and alkaline phosphatase. 
     
     
         14 . The method according to  claim 7 , wherein a peptide conjugate molecule is selected from the group consisting of: avidin, streptavidin, biotin, hexa-His, glutathione S-transferase (GST), and FLAG. 
     
     
         15 . The method according to  claim 7 , wherein the HGF-binding reagent is a nucleic acid operable to hybridize to at least a portion of an HGF gene and the nucleic acid comprises a nucleotide of SEQ ID NOs: 1 or 2. 
     
     
         16 . The method according to  claim 2 , wherein the level of expression of HGF in the biological sample is measured by immunohistochemistry (NC), enzyme linked immunosorbant assay (ELISA), reverse transcription-polymerase chain reation (RT-PCR), microarray analysis, in-vivo molecular imaging, or combinations thereof. 
     
     
         17 . The method according to  claim 2 , wherein the reference sample is selected from the group consisting of a tissue-matched healthy control, a tissue-matched sample of the subject prior to diagnosis of cancer, and a tissue-matched sample of the subject prior to treatment. 
     
     
         18 . The method according to  claim 1 , wherein the Met-related cancer is glioblastomamultiforme. 
     
     
         19 . The method of  claim 1 , further comprising administering a therapeutically effective amount of a Met inhibitor to treat the Met-related cancer in the subject if it is detected that the Met-related cancer is HGF-autocrine. 
     
     
         20 . The method according to  claim 1 , wherein an HGF-binding reagent is administered directly to the subject to detect whether the Met-related cancer is HGF-autocrine. 
     
     
         21 . A method for determining the responsiveness of a Met-related glioblastoma cancer in a subject to treatment with a Met inhibitor, the method comprising:
 (a) obtaining a glioblastoma tumor tissue biopsy sample from the subject;   (b) measuring the level of expression of HGF in the biological sample; and   (c) comparing the level of expression of HGF present in the biopsy sample to a reference sample,   wherein if the level of expression of HGF in the biopsy sample is different from the level of expression of HGF in the reference sample, the subject is identified as having a glioblastoma cancer which is sensitive to treatment with a Met inhibitor.   
     
     
         22 . A kit for determining the responsiveness of a Met-expressing tumor to Met inhibition, the kit comprising:
 a container for collecting a biological sample from a subject and a HGF-binding reagent for detecting HGF in the biological sample.   
     
     
         23 . The kit of  claim 22 , wherein the HGF-binding reagent is selected from the group consisting of: an anti-HGF antibody, a nucleic acid operable to hybridize to at least a portion of a HGF gene, a HGF binding protein, and combinations thereof. 
     
     
         24 . The kit of  claim 23 , wherein the HGF-binding reagent further comprises a detectable tag. 
     
     
         25 . The kit of  claim 24 , wherein the detectable tag is selected from the group consisting of: a fluorophore, a radioligand, a chemilluminescence molecule, a conjugated enzyme, a peptide conjugate molecule, and combinations thereof. 
     
     
         26 . A method of treating glioblastomamultiforme (GBM) in a subject in need thereof, the method comprising:
 administering a therapeutically effective dose of a Met inhibitor in combination with a therapeutically effective dose of a epithelial growth factor receptor (EGFR) inhibitor.   
     
     
         27 . The method according to  claim 26 , wherein the Met inhibitor is administered prior to or subsequent to the administration of the EGFR inhibitor. 
     
     
         28 . The method according to  claim 26 , wherein the Met inhibitor is administered concomitantly with the EGFR inhibitor.